Molecular Mechanisms of Exercise Benefits to Insulin Resistant People

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PROJECT SUMMARY It has been well established that Alzheimer’s disease and other dementias are substantially higher in people with insulin resistance. Insulin resistance occurs in almost 80% of people with Alzheimer’s disease. Both aerobic exercise and resistance exercise training improve peripheral insulin sensitivity and have a beneficial effect on cognition. Although several studies have shown that aerobic exercise in both animals and humans improves brain glucose uptake and mitochondrial function, it is currently unknown whether resistance exercise has any direct effect on brain biology that can contribute to improved cognitive functions. In the current application, we propose to collect preliminary data to plan future larger studies to test the hypothesis that resistance exercise which improves peripheral insulin sensitivity also increases insulin sensitivity in the brain as measured by 18-FDG PET scanning. In addition, we will determine whether the same areas in the brain showing improved glucose uptake also have evidence of enhanced mitochondrial energy metabolites and other biomarkers of neuronal health. We will use structural MRI as well as phosphorus and proton MR spectroscopy to measure brain microstructure and metabolites in brain regions rich in insulin receptors such as cortex and hippocampus. In addition, we also will measure functional connectivity between different regions of the brain by functional MRI to test a hypothesis that improving insulin sensitivity and enhanced energy metabolism in the brain will improve connectivity between different regions of the brain and that this improved connectivity is related to improvements in cognition. All the techniques proposed in the current study are well established at our institution where the PI collaborated with neuro-radiologists and nuclear medicine experts to perform studies in type 1 diabetes showing that insulin deficiency-related changes on brain energetics and functional connectivity concurrent to cognitive changes. In the current study we propose to measure MRI (structural and functional), MR spectroscopy and 18-FDG PET scans as well as neuropsychological tests using NIH Tool box in 24 insulin resistant participants who are part of an NIH RO1 grant to study the mechanism of resistance exercise training effects on peripheral insulin sensitivity. We propose that this is a very cost-effective approach to obtain currently non-existent preliminary data to move forward with further larger studies to understand how resistance training improves cognition by measuring brain connectivity, energetics, and microstructure. The only additional expenses for this study are related to the neuroradiology involving MR measurements and radioisotope-based glucose uptake studies based on PET scan. The results from this study will allow us to determine whether there is sufficient preliminary data to support our hypothesis that resistance exercise training improves brain functions and cognitive functions in insulin resistant people.